Acute myelogenous leukemia (AML) is the most common/highly frequent (onset rate) adult leukemia, characterized by the clonal expansion of immature myeloblasts initiating from rare leukemic stem cells (LSCs) (non-patent documents 1-3). The functional and molecular characteristics of human LSCs are largely undetermined.
While murine leukemia models have provided valuable insights into leukemogenesis, direct in vivo study of primary human leukemia is necessary to understand pathogenic mechanisms unique to human leukemogenesis (non-patent document 4). However, since existing immunodeficient strains such as CB17/SCID (non-patent document 5), NOD/SCID (non-patent documents 6-8) and NOD/SCID/β2mnull (non-patent document 9) with short life spans and age-dependent leakiness of humoral immunity make it difficult to achieve a high engraftment rate of primary human AML, and extremely difficult to perform long-term assessment of primary human AML.
Shultz et al. recently developed a novel immunodeficient mouse strain carrying a complete null mutation of the common cytokine receptor γ chain upon the scid background that leads to a lack of both acquired and innate immunity. In addition, we created a novel immunodeficient strain with improved long-term xenogeneic engraftment, NOD.Cg-PrkdescidIl2rgtm1Wjl/J(NOD/SCID/IL2rγnull) mice, carrying a complete null mutation of the common γ chain (non-patent document 10) (non-patent document 11). This strain, with life expectancy of >90 weeks, is more robust than strains such as NOD/SCID (non-patent document 12), NOD/SCID/β2mnull (non-patent document 13), NOD-Rag1null (non-patent document 14) and NOD-Rag1nullPrf1null (non-patent document 15), allowing assessment of the reconstitution and lymphoid/myeloid differentiation capacity of human long-term repopulating HSCs (LT-HSCs) (non-patent documents 4, 16).
Although conventional chemotherapeutic agents can temporarily remit AML, recurrence later is the difficult problem that prevents us from helping patients. For the development of an effective therapeutic agent or treatment method, elucidation of the recurrence mechanism by clarifying the leukemia features unknown to date is strongly desired. To achieve the goal, the development of an animal model capable of reproducing features of human, rather than mouse, AML, particularly AML of individual patients, rather than a cell line, and permitting long-term assessment is essential.    non-patent document 1: Passegue, E., Jamieson, C. H., Ailles, L. E. & Weissman, I. L. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics Proc Natl Acad Sci USA 100 Suppl 1, 11842-11849 (2003).    non-patent document 2: Hope, K. J., Jin, L. & Dick, J. E. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 5, 738-743 (2004).    non-patent document 3: Jordan, C. T. & Guzman, M. L. Mechanisms controlling pathogenesis and survival of leukemic stem cells. Oncogene 23, 7178-7187 (2004).    non-patent document 4: Huntly, B. J. et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6, 587-596 (2004).    non-patent document 5: Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645-648 (1994).    non-patent document 6: Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3, 730-737 (1997).    non-patent document 7: Ailles, L. E., Gerhard, B. & Hogge, D. E. Detection and characterization of primitive malignant and normal progenitors in patient with acute myelogenous leukemia using long-term coculture with supportive feeder layers and cytokines. Blood 90, 2555-2564 (1997).    non-patent document 8: Lumkul, R. et al. Human AML cells in NOD/SCID mice: engraftment potential and gene expression. Leukemia 16, 1818-1826 (2002).    non-patent document 9: Feuring-Buske, M. et al. Improved engraftment of human acute myeloid leukemia progenitor cells in beta 2-microglobulin-deficient NOD/SCID mice and in NOD/SCID mice transgenic for human growth factors. Leukemia 17, 760-763 (2003).    non-patent document 10: Cao, X. et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity 2, 223-238 (1995).    non-patent document 11: Ishikawa, F. et al. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice. Blood 106, 1565-1573 (2005).    non-patent document 12: Shultz, L. D. et al. Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol 154, 180-191 (1995).    non-patent document 13: Christianson, S. W. et al. Enhanced human CD4+ T cell engraftment in beta 2-microglobulin-deficient NOD-scid mice. J Immunol 158, 3578-3586 (1997).    non-patent document 14: Shultz, L. D. et al. NOD/LtSz-Rag1null mice: an immunodeficient and radioresistant model for engraftment of human hematolymphoid cells, HIV infection, and adoptive transfer of NOD mouse diabetogenic T cells. Journal of Immunology 164, 2496-2507 (2000).    non-patent document 15: Shultz, L. D. et al. NOD/LtSz-Rag1nullPfpnull mice: a new model system with increased levels of human peripheral leukocyte and hematopoietic stem-cell engraftment. Transplantation 76, 1036-1042 (2003).    non-patent document 16: Shultz, L. D. et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol 174, 6477-6489 (2005).